tbuckley/cabot-search huggingface dataset:
Abstract 5444: BPI-371153, an orally bioavailable small molecule PD-L1 inhibitor
Authors: Yiqian Wang, Xiangyan Jing, Hong Chen, Huijuan Zhang, Tianyi Ma, Yao Zhang, Chunhui Zhang, Guangzhi Zhang, Xiangyong Liu, Dan Yan, Jing Guo, Hong Lan, Jiabing Wang, Lieming Ding
Journal: Cancer Research (2022)

Abstract PD-1/PD-L1 antibodies have entered mainstream of cancer treatment, but they came with limitations such as weak tumor penetration, immunogenicity, immune-related risks with a long half-life, and high cost. Small molecule inhibitors of PD-L1 are expected to overcome these limitations. We hereby present BPI-371153, an orally bioavailable small molecule that disrupts PD-1/PD-L1 interaction similar to PD-1/PD-L1 antibodies. BPI-371153 demonstrates high binding affinity to human PD-L1, induces PD-L1 dimeralization and disrupts PD-L1:PD-1 interaction (IC50 &amp;lt;1 nM by HTRF assay). BPI-371153 induces PD-L1 internalization with an IC50 value of 4.2 nM as detected by flow cytometry, activates nuclear factor of activated T cell (NFAT) signaling in cell-based reporter assay, and effectively stimulates IFN-γ release in human peripheral blood monocyte-mediated tumor cell killing assay. In a syngeneic mouse model with murine MC38 colon tumor cells expressing human PD-L1 (MC38-hPD-L1 model), BPI-371153 suppressed tumor growth to an extent comparable to an anti-PD-L1 antibody. In immunocompromised mice grafted with the same cell line, no growth inhibition was observed, confirming that the pharmacologic effect of BPI-371153 indeed came from the immune system. In addition, this compound exhibits favorable ADME properties, with high oral exposure across multiple pre-clinical species. Phase I clinical trial of BPI-371153 is planned for early 2022. Citation Format: Yiqian Wang, Xiangyan Jing, Hong Chen, Huijuan Zhang, Tianyi Ma, Yao Zhang, Chunhui Zhang, Guangzhi Zhang, Xiangyong Liu, Dan Yan, Jing Guo, Hong Lan, Jiabing Wang, Lieming Ding. BPI-371153, an orally bioavailable small molecule PD-L1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5444.
Abstract 3008: Induction of necroptosis through caspase-independent mechanisms in MCF-7 breast cancer cells following HDAC inhibition
Authors: Umamaheswari Natarajan, Grace Waldron, Thiagarajan Venkatesan, Appu Rathinavelu
Journal: Cancer Research (2022)

Abstract Cell proliferation and cell death are essential for maintaining homeostatic balance in eukaryotic organisms. Many diseases develop when cellular homeostasis is disturbed. Currently, several anti-cancer drugs are known to induce apoptosis through activation of intrinsic or extrinsic pathways. However, many types of cancer cells have acquired resistance due to quick adaptation to resist pro-apoptotic mechanisms. Therefore, simultaneous induction of other forms of cell deaths such as necroptosis, autophagy, etc., in addition to apoptosis, is becoming an attractive strategy for controlling tumor growth and metastasis. For this purpose, we have explored the role of XIAP in caspase-independent mechanisms of cell death during HDAC (Histone Deacetylase) inhibition. Our experiments with HDAC inhibitor SAHA (Suberoylanilide hydroxamic acid) have revealed that the anti-apoptotic biomarkers, including survivin and XIAP, exhibit important regulatory functions for inducing necroptosis in cancer cells. Interestingly, many of the signal adaptors of apoptosis and necroptosis are known to show dual functions during drug-induced cancer cell death. For example, the formation of the survivin-XIAP complex prevents XIAP from undergoing proteasomal degradation and polyubiquitination, thereby stabilizing XIAP in cancer cells. When the survivin level is increased, it is also known to stop the inhibition of XIAP by Smac. In addition, since XIAP can inhibit caspase -9 and the executioner caspases -3 and -7, the apoptosis mechanisms will be blocked, and cell proliferation will continue to promote cell survival and tumorigenesis. Our western blot data revealed that the caspase -9, -3, -7, and -8 levels were significantly downregulated in MCF-7 breast cancer cells following SAHA treatment. Furthermore, SAHA treatment also increased the levels of necroptosis inducers such as phospho-RIP3 and MLKL in MCF-7 cells. However, treatment of the same MCF-7 cells with other drugs such as RG-7388, an MDM2 inhibitor, was able to induce apoptosis through activation of caspases. Our current results show that MCF-7 cells may switch to the necroptosis pathway due to the inhibition of caspases and increased levels of survivin and XIAP. (This research was supported by the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida). Citation Format: Umamaheswari Natarajan, Grace Waldron, Thiagarajan Venkatesan, Appu Rathinavelu. Induction of necroptosis through caspase-independent mechanisms in MCF-7 breast cancer cells following HDAC inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3008.
Abstract 5299: A therapeutic antibody against G-protein-coupled receptor class 5 member D to treat multiple myeloma
Authors: Feng He, Kefei Wu, Jiabei Liang, Jianhui Li, Hao Peng, Guojin Wu, Jinying Ning
Journal: Cancer Research (2022)

Abstract Multiple myeloma (MM) comprised 0.9% of all new cancer cases and 1.2% of cancer death in 2020 and is the second most common hematological neoplasm in adults. Primary refractory to treatment and relapse resulted in a high death rate of MM patients. Bispecific antibodies (BsAbs) are attracting candidate drugs against multiple myeloma by targeting CD3 on T cells and MM specific cell surface markers such as B cell maturation antigen (BCMA), CD38, and G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D). In the current study, we developed a humanized antibody targeting GPRC5D (clone number G-02-9D7). The antibody was derived from hybridoma of mouse immunized with GPRC5D overexpressed mouse cell line. Compared to the GPRC5D antibody in clinical (JNJ-64407564), this antibody has a higher affinity to 293T cells overexpressing GPRC5D (EC50=1.9nM vs. 3nM), MM cell lines, and MM patient samples. In addition, this antibody did not bind to GPRC5A, B, and C and had weaker non-specific binding to human serum albumin than JNJ-64407564. Bispecific antibody derived from the GRPC5D antibody and CD3 antibody (clone number: sp34) induced specific cytotoxicity of MM cells in the presence of T cells from PBMC. This bispecific antibody stimulated the release of cytokines from T cells such as INF-γ, IL-2, IL-8, and TNF-α. In NCI-H929 prophylactic xenograft mouse model with PBMC transplantation, tumor growth could be prevented by administration weekly with this bispecific antibody as low as 0.1ug per mouse. In the presence of T cells, the bispecific antibody also resulted in complete remission of established MM.1S tumor in xenografted NSG mouse with the injection of 1ug antibody weekly. At last, MM patient bone marrow samples cultured in vitro with this bispecific antibody increased cell death of the CD138+ population. In summary, the GPRC5D antibody could efficiently target Multiple myeloma tumor cells. Citation Format: Feng He, Kefei Wu, Jiabei Liang, Jianhui Li, Hao Peng, Guojin Wu, Jinying Ning. A therapeutic antibody against G-protein-coupled receptor class 5 member D to treat multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5299.
Abstract 1937: DIME-CT: Self-supervised learning for medical image analysis using patch-based embeddings
Authors: Leon Fedden, Zhenning Zhang, Khan Baykaner, Qin Li, Lucas Bordeaux
Journal: Cancer Research (2022)

Abstract Whether tracking patient progress for clinical decision making, or investigating novel therapies, automated analysis of Computed Tomography (CT) imaging data is essential for the future of digital radiomics. In digital radiomics, as in all medical imaging, well annotated data is scarce, whereas unlabelled images are relatively plentiful. In other fields of image processing and medical imaging, the application of self-supervised learning (SSL) to large quantities of unlabelled data has resulted in great strides forward for fast, scalable, and interpretable image analysis. In this work we present a new approach applying SSL to CT imaging data which allows for: 1) Improved performance on image classification tasks, based on 2) dramatically reduced quantity of annotated CT imaging data, whilst also 3) enabling easy exploration and interpretation of the image regions. We applied a selection of self-supervised approaches (BYOL, DINO, SimCLR, &amp; inpainting) to CT imaging data. Because the high dimensionality of CT data prevents us from using them directly to out-of the box SSL models, we adopt a 3D patching approach to reduce the dimensionality of the neural net input, and process each patch independently. We train our self-supervised models on public datasets (DeepLesion, NSCLC), and we specialize these models for tumor classification tasks that we evaluate on AstraZeneca sponsored clinical trials. The specialization is done in two different ways: 1) we use the pre-trained SSL model as an encoder that transforms the images of the clinical study into embeddings, on which we apply supervised classification models; 2) we use transfer learning to fine-tune supervised classification models that take the patches directly as inputs. We find that self-supervised pre-training significantly improves the accuracy on tumor classification tasks compared against a supervised learning baseline. Additionally, using the SSL embeddings we build an interactive map of CT imaging data enabling quick and intuitive inspection of the relevant regions. Our findings show that SSL constitutes an important tool for medical imaging analysis. SSL results in models that generalize better, and enable improved downstream interpretability and predictions. Furthermore, well trained SSL models can be re-applied to multiple indications because they are pre-trained on broad and diverse CT imaging data. Citation Format: Leon Fedden, Zhenning Zhang, Khan Baykaner, Qin Li, Lucas Bordeaux. DIME-CT: Self-supervised learning for medical image analysis using patch-based embeddings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1937.
Abstract 5374: Amentoflavone induces apoptosis and promotes G1 phase cell cycle arrest through regulating p53 pathway in HT29 human colorectal cancer
Authors: Hsiang-Ju Ku, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu
Journal: Cancer Research (2022)

Abstract Amentoflavone (AF) is a nature diflavonoid compound that could extract from Ginkgo biloba and Chamaecyparis obtusa. AF had been proven with many biological properties, including anti-oxidant activity, anti-inflammatory, and could also inhibit NF-κB mediating apoptosis to achieve anti-tumor effects in hepatocellular carcinoma. p53, a tumor suppressor gene that could inhibit cell division and proliferation through regulating with cell cycle and apoptosis related molecules. Patients with p53 gene mutation were often resistant to current standard treatment in clinic. Several studies also reported that the activation of p53 could induce apoptosis in colorectal cancer (CRC). Currently, there is no study determine whether AF can inhibit the growth of colorectal cancer by upregulating p53 gene expression. The aim of this study was to investigate the anticancer effect and the underlying mechanism of AF in CRC in vitro and in vivo. First, we indicated the cytotoxic effect was induced by AF in human CRC (HT29) cells. The suppression of metastasis ability including migration and invasion were found to be suppressed by AF treatment group using transwell assay. Also, in colony formation assay, AF inhibited the proliferation of CRC cells. The tumor suppressor gene p53 was upregulating with AF treatment, and the cell cycle related protein, such as CyclinD1 and CDK4 were all downregulated by AF which identified by Western blotting assay. Additionally, AF induced apoptosis in CRC cells were detected by Western blotting and flow cytometry with cleaved caspase-3, -8, -9 and Annexin V/PI assay. Moreover, Western blotting results indicated that DNA damage proteins (cleaved PARP-1 and ATM) were upregulated by AF. The nucleus translocation of caspase-dependent mitochondria initiated apoptotic protein (EndoG and AIF) were induced by AF in CRC cells. In animal experiments, the CRC tumors volume were effectively reduced in AF treatment groups as compared to non-treated control. In summary, AF mediated anti-CRC effects, such as inhibiting cell proliferation, suppressing migration/invasion ability, inducing apoptosis and triggering DNA damage is associated with the induction of p53. Citation Format: Hsiang-Ju Ku, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Amentoflavone induces apoptosis and promotes G1 phase cell cycle arrest through regulating p53 pathway in HT29 human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5374.
A Commentary on “Non-technical skills in surgery during the COVID-19 pandemic: An observational study” (Int J Surg 2022;98:106210)
Authors: Juliana Hernández Monroy, María Camila Amaya Muñoz, Miguel Andres Vargas Riascos, Gonzalo Andrés Domínguez Alvarado
Journal: International Journal of Surgery (2022)
Abstract 2007: Use of an anti-IL-10 antibody to improve Mifamurtide efficacy on aggressive osteosarcoma cells
Authors: Nicoletta Nastasi, Angela Subbiani, Maria Letizia Taddei, Lucia Scala, Angela Tamburini, Claudio Favre, Maura Calvani
Journal: Cancer Research (2022)

Abstract Osteosarcoma is a primary malignant bone tumor highly aggressive and metastasizing, composed of mesenchymal cells producing osteoid and immature matrix. Osteosarcoma is the most frequent bone tumor and it mainly affects children and adolescents. The main treatment option is a combination of surgery and chemotherapy. Research into new therapeutic strategies to improve the quality of life of patients is currently underway. The development of the anti-tumor immunostimulant drug Mifamurtide is part of this research. There are very conflicting opinions on the therapeutic validity of this drug. Therefore, we tested experimentally the effectiveness of Mifamurtide in three cell lines of osteosarcoma (MG-63, HOS, 143B) with different grades of malignancy, grown in co-culture with macrophage to allow the correct internalization of the drug. Through in vitro experiments, we analyzed the effects of Mifamurtide on tumor cell viability, on cellular signaling pathway and on macrophage polarization. Results show that Mifamurtide loses its effectiveness as the tumor malignity increases. The most aggressive tumor cells are not affected by the therapy, probably because they implement methods of resistance to apoptosis. Furthermore, they would be able to affect the tumor microenvironment to their own advantage. To better understand Mifamurtide impact on tumor microenvironment, we also performed a cytokine assay on the culture medium in which the cells grew. The most significant results were identified in the interleukine-10 (IL-10): IL-10 is expressed in higher quantities in the highest-grade osteosarcoma cells. This anti-inflammatory cytokine can inhibit the synthesis of pro-inflammatory cytokine and suppresses the antigen presentation capacity of APC cells. This allows cancer cells to evade immune surveillance mechanisms. In vivo and in vitro results show that the synergic use of an anti-IL-10 antibody in combination with Mifamurtide can improve its efficacy. Here, we provide experimental evidence that the addition of an anti-IL-10 antibody to Mifamurtide causes a significant death rate in more aggressive osteosarcoma cells and lower metastasis, compared to Mifamurtide only. In conclusion, considering our data, it could be proposed a new treatment protocol for metastatic osteosarcoma that includes the use of an anti-IL10 antibody integrated with the administration of Mifamurtide to increase its effectiveness in this clinical context. Citation Format: Nicoletta Nastasi, Angela Subbiani, Maria Letizia Taddei, Lucia Scala, Angela Tamburini, Claudio Favre, Maura Calvani. Use of an anti-IL-10 antibody to improve Mifamurtide efficacy on aggressive osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2007.
Abstract 2899: Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors
Authors: Roshan M. Kumar, Julie Prigent, Hombline Poullain, Ayrin Kok, Carine George, Sami Ellouze, Yun-Yueh Lu, Rebecca Silver, Clarisse Monchecourt, Ross B. Fulton, Qian Zhang, Nicola Beltraminelli, Bernhard Moser, Francisco Adrian, Liang Schweizer
Journal: Cancer Research (2022)

Abstract Regulatory T cells (Tregs) contribute to immunosuppression within the tumor microenvironment and have been associated with poor outcomes in a range of cancers. Targeted depletion of tumor-infiltrating Tregs (TITRs) is an attractive therapeutic strategy with the potential to enhance antitumor immunity in patients who do not respond to current treatments. However, such approaches have been limited to date by a lack of markers that are highly specific for TITRs. CCR8 is a chemokine G protein-coupled receptor (GPCR) that has recently been shown to be specifically expressed on TITRs as compared to Tregs in the periphery or other T cells within tumors. Here, we report the development and characterization of HFB101110, a humanized monoclonal antibody against CCR8 with potent and specific antibody-dependent cellular cytotoxicity (ADCC) activity. HFB101110 specifically recognizes an epitope on the N-terminus extracellular domain of CCR8 and does not recognize the closely related chemokine receptor CCR4. HFB101110 acts through a dual mechanism of action, by both depleting CCR8+ cells via ADCC and blocking binding of the CCL1 chemokine to its receptor CCR8. Blockade by HFB101110 inhibited calcium flux and chemotaxis induced by the interaction between CCL1 and CCR8. Furthermore, HFB101110 showed potent single agent anti-tumor activity associated with depletion of intratumoral Tregs in a human CCR8 knock-in mouse model. HFB101110 mediated specific ex vivo killing of Tregs from primary patient tumor samples both in the presence, and in some cases the absence, of allogeneic NK cells. HFB101110 showed favorable pharmacokinetic properties and a favorable developability profile, and was well-tolerated in both wild-type mice and cynomolgus monkeys. HFB101110 is currently being developed as a novel immunotherapy for the treatment of solid tumors coupled with a patient biomarker strategy derived from HiFiBiO’s Drug Intelligent Science (DIS™) single-cell immune profiling platform. Citation Format: Roshan M. Kumar, Julie Prigent, Hombline Poullain, Ayrin Kok, Carine George, Sami Ellouze, Yun-Yueh Lu, Rebecca Silver, Clarisse Monchecourt, Ross B. Fulton, Qian Zhang, Nicola Beltraminelli, Bernhard Moser, Francisco Adrian, Liang Schweizer. Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2899.
Abstract 2379: Gender-specific metabolome in bladder cancer: Role of EPHX2 in bladder cancer
Authors: Mohammed Khurshidul Hassan, Roshan Borkar, Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Chandra Shekar Amara, Allison Bellman, ChandraShekar R. Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Roni J. Bollag, Martha K. Terris, Leomar Y. Ballester, Yair Lotan, Cristian Coarfa, Arun Sreekumar, Nagireddy Putluri
Journal: Cancer Research (2022)

Abstract Bladder cancer (BLCA) is the fourth most common cancer diagnosed in American men. In the U.S., men are four times more likely to be diagnosed with bladder cancer than women. Our research group has previously identified alterations in xenobiotic metabolism in BLCA. In this study, using a metabolomics approach, we identified alterations in the arachidonic acid pathway in bladder tumors from male versus female patients. Included within this altered arachidonic acid pathway was downregulation of EPHX2, an enzyme that converts epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DiHETs). Consistent with this, levels of EETs were significantly elevated in bladder tumors derived from male versus female patients. Cox proportional hazard regression analysis further revealed that reduced expression of EPHX2 was significantly associated with poor clinical outcome across multiple publicly available datasets only in male BLCA patients but not in females. Mechanistic studies revealed that EPHX2 over-expression in male-derived BLCA cell line reduced cell growth in vitro and tumor growth in vivo. Overall, these studies nominate EPHX2 as a potential tumor suppressor in male patients with BLCA. Citation Format: Mohammed Khurshidul Hassan, Roshan Borkar, Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Chandra Shekar Amara, Allison Bellman, ChandraShekar R. Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Roni J. Bollag, Martha K. Terris, Leomar Y. Ballester, Yair Lotan, Cristian Coarfa, Arun Sreekumar, Nagireddy Putluri. Gender-specific metabolome in bladder cancer: Role of EPHX2 in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2379.
Abstract 6010: Mouse hind limb tumor metastatic model to evaluate prophylaxis and treatment
Authors: Yao Shuai, Chaomeng Wang, Ling Tong, Qiao Liu, Jie Xu, Qunsheng Ji
Journal: Cancer Research (2022)

Abstract We have established and optimized a robust tumor bone metastasis mouse model, which recapitulates the tumor metastasis progression from circulation to bone colonization, and provides windows for both prophylaxis and treatment. Specifically, we inoculated two breast cancer cell lines, JIMT-1 and MDA-MB-231, each with high metastatic potential, into mouse intra-caudal artery. By detection of steadily incremental bioluminescence signal, prophylaxis was observed to precede metastases, which were found exclusively on mouse hind limbs. These mouse models exhibited swollen hind limbs and even paralysis at late stage. Gross necropsy and pathology analysis confirmed the exclusive hind limb localization, the invasion and spreading of tumor cells to muscles and bone marrows, and the lesions in tibias and femurs. Our robust bone metastases models thus imitate the multiple stages of tumor metastasis, leading to exclusion bone metastasis and opening up windows for prophylaxis and treatment. Citation Format: Yao Shuai, Chaomeng Wang, Ling Tong, Qiao Liu, Jie Xu, Qunsheng Ji. Mouse hind limb tumor metastatic model to evaluate prophylaxis and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6010.